PharmPK Discussion - Omeprazole bioavailability

On 11 Dec 2000 at 14:33:08, "radhakrishna bangaru" (brkrish.-at-.rediffmail.com) sent the message

Dear Sir,

we have done some studies on bioequivalency of Omeprazolecapsul 20 mg in human subjects as 2 way crossover study. The 90%Confidence Intervals for Cmax are 110-141%, and AUC(0--->t) and AUC0--->inf are 87-115% and 87-118% respectively. The power valueis >0.8 and there are some references saying Cmax is not correlatedwith antisecretary activity where as AUC is to some extent Correlatedwith it.

Looking at the above results should we make decision as the twoformulations are bio-inequivalents? . Please let give your opinionand FDA's perspective in this regard.

clearly bioinequivalent: you ned clinical data to get approval.........studyin humans of gastric pH and Prilosec. (505 b2 submission)I have submitted two NDA in the last 5 years on bioavailability typesubmissions.

I am available for consulting work since I now have my own business. Theagency is 20 minutes from my house here in Maryalnd.

On 11 Dec 2000 at 19:19:11, Gilberto De Nucci (denucci.-a-.dglnet.com.br) sent the message

I would take the following points into consideration:

i - omeprazole has a large therapeutic index, thus the higher Cmaxyou observed is unlikely to cause any adverse event. Indeed, for somehighly variable drugs, the interval proposed for Cmax is 70-143%.ii - with chronic use, the Cmax will fluctuate less and thisdifference you have observed between the two formulations shouldbecome smaller.iii - AUC intervals are within the 80-125%.

My conclusion is that I would accept this formulation as bioequivalent.

Results suggest faster absorption but similar extent. Clearly Cmax does notfall within the 80-125% acceptance criteria applied to AUC but this may bean example where widening the criteria for Cmax to the suggested 70-143% isappropriate. On the face of it worth putting a case together and discussingwith the regulatory authority.

On 13 Dec 2000 at 10:37:00, =?iso-8859-1?Q?=22Jes=FAs_Fr=EDas_Iniesta=22?= (jesus.frias.at.uam.es) sent the message

The following message was posted to: PharmPK

We have done six bioequivalence studies (crossover single dose, multipledose and food interaction), always with the same reference, and since thispoint of view we should say that these results are quite good foromeprazole. Another thing is the decisi=F3n of bioequivalence, since this is= aregulatory convenience, although probably both formulation areinterchangeable. We should discuss with the authorities the relevance ofCmax in omeprazole effects (see Lind and cols, 1983 and Londong andcols,1983) and the value of IC limits of 80-125 for drugs with highinterindividual variability (see Steinijans and Hauschke 1993). Another way to disccuss the results is to test the bioequivalencehypothesis about early exposure calculating truncated AUC till medianreference population Tmax, according to the last bioequivalence FDAguideline of October 2000.

On 13 Dec 2000 at 10:50:50, Art Straughn (ASTRAUGHN.aaa.utmem.edu) sent the message

Reformulate!! You will be wasting your time trying to convince anyonethat the products are bioequivalent when the test product is clearlynot acceptable. Even if you go to a replicate study, I doubt (just ahunch without complete stat analysis) the reference will show enoughwithin subject variability to justify a widening of the CI. Finally, Iwould worry that a replicate study with this formulation would show a SX F interaction. Do the Gore thing and come back with a betterplatform.

Art StraughnProfessor and DirectorDrug Research Laboratory (DRL)University of Tennessee

=46irst the approved form of omeprazole is acid labile and is formulatedas delayed release beads.Second the study was done with an omeprazole dose of 20 mg. Howeveromeprazole exhibits nonlinear kinetics at doses above 40 mg (well withinthe labeled dosage range). In addition, nonlinearity is see at lowerdoses in certain populations, probably due to polymorphic metabolism.

Regarding correlation of effect with AUC. So what. It was simply asimple correlation. In judging the clinical significance of anydifference in BA I would wonder about the drug receptor bindingkinetics. Based upon the mechanism I would suspect time to and durationabove a certain minimum concentration may be more meaningful.

I would recommend that the original poster take a look at the new FDAguidance:

Regarding the widening the acceptance criteria. The FDA guidancementioned above is now recommending replicate designs for highvariability drugs without any widening of the acceptance criteria beyond80 - 125.